DE2422385C2 - 7- (Substituted phenylglycine amido) -3-methyl-3-cephem-4-carboxylic acid derivatives, processes for their preparation and pharmaceuticals containing them - Google Patents

Description

COOM

where mean:

Ri a (Ci-iVAIkansulfonamido- or (Ci- ₂ ) -Alkylureido group,

Ri is a hydrogen atom or a hydroxyl group, and

M represents a hydrogen atom or a non-toxic pharmaceutically acceptable cation.

2. 7- [D- (3-Mesylaminophenyl) -glycineamido] -3-methyl-3-cephem -4 -carboxylic acid.

3. 7-! 2- (3-Mesylamino-4-hydroxyphenyl) -D-glycineamido] -3-methyl-3-cephem-4-carboxylic acid.

4. 7- [2- {3- (3-! Vlethylureido) phenyl} -D-glycinamido] -3-methyl-3-cephem-4 -carboxylic acid.

5. Process for the preparation of the compounds according to one of claims 1 to 4, characterized in that that in a known manner 3-methyl-7-amino-3-cephem-4-carboxylic acid the formula

CH ₃

COOH

or a salt or ester thereof or its reaction product with a silyl compound with substituted Phenylglycine of the general formula

CH-COOH

NH ₁

20 describes the S-heterocyclothiomethylcephalosporins. These compounds were found to be antibiotic, as was the cefadroxil described in GB-PS 12 40 687.

The invention relates to the 7- (substituted phenylglycineamido) -3-methyl-3-cephem-4-carboxylic acid derivatives as defined in the claims of the general formula 1, which are characterized by a surprisingly good oral absorption capacity and antibacterial effect.

_{The (C | _ 2} ) alkanesulfonamido group shown in the general formula 1 and R 1 means a mesylamino or ethanesulfonamido group. The (C-O-alkyl radicals of the (C, _,) alkylureido group represented by R, are the same as those in the above-mentioned (C] _ ₂ ) alkanesulfonamido group.

The non-toxic pharmaceutically acceptable cation represented by M means e.g. B. an Alkalimeiallkalion like the cation of sodium or potassium.

The compounds of general formula I according to the invention can be prepared by reacting 3-methyl-7-amino-3-cephem-4-carboxylic acid the formula

25th

35

45

50

where R, and R? the meanings given in claim 1 and in which the amino group is optionally is protected in the usual way, or converted its salt, acid halide or acid anhydride and the amino protective group which may be present is removed from the reaction product will.

6. Medicinal product, characterized in that it a compound according to any one of claims 1 to 5 and a pharmaceutically acceptable, non-toxic one Contains carrier or excipient.

65

In DE-OS 16 70 625 3-methylccphalosporins and in DE-OScn 20 18 600 and 21 62 575 wcr-NH

CH,

30 COOH

or a salt or ester thereof or its reaction product with a silyl compound with substituted Phcnylglycine of the general formula

40

in which R _{1 and R 2 have} the definition according to the claims, and in which the amino group is optionally protected in the customary manner. or its salt. Acid halide or acid anhydride, are prepared, the amino protective group that may be present being removed from the reaction product. Η customary amino are, for example, a Bcnzyloxycarbonyl-, substitucrtc benzyloxycarbonyl, Alkoxycai ¹ onyl-, substituted alkoxycarbonyl, aralkoxycarbonyl, Adamantyloxyaubonyl-, trityl, substituted phenylthio, substituted aralkylidene, substituted alkylidene or substituted Cycloalkylidcngruppe ·.

The salts of compound 11 are e.g. B. the magnesium salt, calcium salt or triethylamine salt. Examples of esters are the methyl ester and ethyl ester. Propylesicr. Butyl ester, pentyl ester, trimethylsilyl ester. 2-mesylethyl ester, 2-iodoethyl ester, 2,2.2-trichloroethyl ester, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenacyl ester, phenethyl ester, trilyl ester, di-phenyl methyl ester, bis (methoxyphenyl) methyl ester. 3,4-Dimethoxybenzyl ester, (1-cyclopropyl-ethyl ester, ethynyl ester and "i-HydroxyO.S-di-tert-butylbenzyl ester.

As a reaction product of the compound 11 with a silyl compound, for example, that with His-urimethylsilvD-acetamide be used.

An example of acid halides of the substituted

Phenylglycine of the general formula III is the acid chloride; the acid anhydrides can be mixed acid anhydrides with an acid such as dialkyl phosphoric acid, Phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, Halogenated phosphoric acid, dialkylphosphoric acid, sulphurous acid, thiosulphuric acid. Sulfuric acid, alkyl carbonic acid, aliphatic carboxylic acids such as pivalonic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroesslgic acid; or with aromatic carboxylic acids such as benzoic acid or symmetrical acid anhydrides.

The reaction is usually carried out in a solvent such as acetone, dioxane, acetonitrile, chloroform, methylene chloride, Ethylene chloride, tetrahydrofuran, ethyl acetate, dimethylformamide, pyridine or any other organic solvent which is inert to the reaction carried out. Among these solvents For example, hydrophilic solvents can be used in the form of a mixture with water.

If the substituted phenylglycine of the general formula III in the form of the free acid or its salt in this reaction is used, the reaction is preferably carried out in the presence of a condensing agent, such as N.N'-Dicyclohexylcarbodilmld, N-Cyclohexyl-N'-morpholinoäthylcarbodilmld, N-Cyclohexyl-N '- <4-diethylamlnocyclohexyO-carbodiimide, Ν, Ν'-Diethylcarbodlimid, Ν, Ν'-Dllsopropylcarbodiimid, N-Ethyl-N '- (3-dimethylamlnopropyD-carbodlimld, N, N'-carbonyldi (2-methylimidazole), pentamethylene ketene-N-cyclohexyl-1min, Diphenylketene-N-cyclohexylimine, alkoxyacetylene, 1-alkoxy-1-chloroethylene, Trlalkylphosphl, Ethylpolyphosphat, Isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, thionyl chloride. Oxalyl chloride, triphenylphosphine, 2-ethyl-7-hydroxybenzlsoxazolium salt, the intramolecular salt of 2-ethyl-5- (m-sulfophenyl) -lsoxazolum hydroxide or (chloromethylene) dimethylammonium chloride. As the salt of the substituted Phenylglydns III can be an alkali metal salt, alkaline earth metal salt, ammonium salt, a salt with an organic Bast: such as methylamine or dicyclohexylamine.

The reaction can be carried out in the presence of a base such as an alkali metal bicarbonate, trialkylamine, N, N-dialkylbenzylamine or pyridine. When the base or the condensing agent is in liquid form is present, it can also be used as a solvent. The reaction temperature is not subject to any Limitation, and the reaction is usually carried out under cooling or at room temperature.

If the reaction product has a protected amino group, the amino protecting group can through Use a suitable cleavage reaction as discussed below from the reaction product removed.

The reaction for removing the amino protective group can be carried out by an ordinary method be, as by decomposition with acids or catalytic reduction, depending on the nature of the Protecting group on the amino group is chosen.

Acid decomposition is one of the most suitable methods and can be used to substituents such as benzyloxycarbonyl, substituted benzyloxycarbonyl, alkoxycarbonyl, substituted Alkoxycarbonyl, aralkoxycarbonyl, adamantyloxycarbonyl, trityl, substituted phenylthlo, substituted To remove aralkyldene, substituted alkyldenene and substituted cycloalkyldene groups. The for the preceding Reaction applied acid will be dependent

is selected from the nature of the protecting group of the amino group, and suitable acids include formic acid and Trifluoroacetic acid, which can be easily evaporated under reduced pressure. When the decomposition through Acid is carried out in a solvent, favorably as the solvent, a hydrophilic organic one Solvent, water or a mixture thereof is used.

The catalytic reduction can be used to remove amino protective groups, such as benzyloxycarbonyl, substituted Benzyloxycarbonyl and 2-pyridylmethoxycarbonyl groups can be used. A suitable catalyst is palladium; but it can also be used other catalysts that are normally used for catalytic Reduction can be used. The trifluoroacetyl group can be formed by treating the reaction product removed with water, and a halogen-substituted alkoxycarbonyl group and 8-quinolyloxycarbonyl group can be removed by the reaction product with a heavy metal, such as copper or zinc.

The reaction for removing the protective group of the amino group can be carried out without that Reaktior.sprodukt is isolated from the reaction medium and purified.

The compounds according to the invention can be converted into their pharmaceutically acceptable, non-toxic salts with the aid of customary methods for salt formation from acids, for example by reaction with an alkali metal hydroxide, alkali metal carbonate, alkali metal carbonate or an organic base, the sodium salt being preferred. The preferred method of preparing the salts is to dissolve the acid in a solvent in which the salt is insoluble and then add a solution of the salt-forming compound or base. In this way the salt is precipitated from the reaction mixture.
The compounds of the invention show high antibacterial activity and inhibit the growth of numerous microorganisms, including gram-positive and gram-negative bacteria. For therapeutic administration, the cephalosporin derivatives according to the invention are used in the form of a pharmaceutical preparation which contains these compounds in admixture with a pharmaceutically suitable organic or inorganic solid or liquid excipient which is suitable for oral or parenteral administration. The pharmaceutical preparations

Can be in solid form, such as capsules, or tablets Dragees, or in liquid form, such as solutions, suspensions or emulsions. If so desired the above-mentioned preparations can contain auxiliary substances, stabilizers, wetting or emulsifying agents

medium, buffers and others commonly used Additives are added.

The dosage of the compounds according to the invention depends on the age and condition of the patient and fluctuates depending on these

ills; an average single dose of about However, 100 mg, 250 mg and 500 mg of the compounds of the invention has been found to be effective for treatment proven of diseases caused by bacterial infection. In general, quantities between 10 mg and about 1000 mg or even more can be administered.

The following examples are intended to illustrate the invention.

example 1

Preparation of the starting compound N-tert-butoxycarbonyl-2- (3-mesylaminophenyl) -D-glycine

8.7 g of N-tert-butoxycarbonyl-2 (3-aminophenyl) -D-glycine and 13.1 g of N-trimethylsilylacetamide were added to 166 ml of methylene chloride was added and the resulting mixture was allowed to stand at room temperature for 1.5 hours touched. To the mixture obtained, 13.1 g of pyridine was added dropwise with ice cooling, and then was added to a solution of 8.45 g of methanesulfonyl chloride in 35 ml of methylene chloride was added dropwise at a temperature of 3 to 5 ° C. It was continued for 30 minutes at the same temperature and then for 4 hours at room temperature touched. The reaction mixture was shaken with an aqueous citric acid solution, with water washed, and then the methylene chloride layer was separated. The methylene chloride layer was coated with a Shaken 596 aqueous sodium hydrogen carbonate solution and the water layer wi-rde separated. the Water layer was adjusted to pH 5 with an aqueous citric acid solution and salted out to form a resinous substance. The resinous substance was extracted with methylene chloride, and the extract was washed with a dilute aqueous solution of sodium chloride, dried and reduced under reduced pressure Concentrated under pressure, 6.3 g of N-tert-butoxycarbonyl-2- (3-mesylaminophenyl) -D-glycine obtained in the form of an amorphous powder, NMR: (DMSO-d ")" 5 ppm: 1.38 (9H, s); 2.99 (3H, s); 5.09 (1H, d, J = 7.5 Hz); 7.00 to 7.60 (4H, m).

Preparation of the 2,2,2-trichloroethyl ester of 7- [D-N-tert-butoxycarbonyl ^ -O-mesylaminophenyD-glycine- amido] -3-methyl-3-cephem-4-carboxylic acid

A) 810 mg of triethylamine and 245 mg of Ν, Ν were added dropwise to a suspension of 3820 mg of the hydrochloride of 2,2,2-trichloroethyl-7-amino-3-methyl-3-cephem-4-carboxyiate in 50 ml of absolute methylene chloride -Dimethylaniline given while stirring and while cooling with ice. The mixture was stirred at room temperature for 30 minutes. 3440 mg of N-tert-butoxycarbonyl-2- (3-mesylaminophenyl) -D-glycine, 1010 mg of triethylamine and 4 drops of N, N-dimethylbenzylamine were added to 50 ml of absolute methylene chloride, and the mixture was cooled with dry ice acetone touched. A solution of 1085 mg of ethylchloroformiate in 25 ml of absolute methylene chloride was. Added dropwise to the mixture at -25 to -30 ⁰ C during 10 min. This mixture was stirred at the same temperature for 15 minutes. The previously prepared mixture, which had been precooled to -15 ° C., was added to the mixture in a single portion. The resulting mixture was stirred for 4 hours at -25 to 30 ° C and then washed with water, 3% hydrochloric acid and again with water. The organic layer was separated, washed in turn with a 396 aqueous solution of sodium bicarbonate and water, and dried. The methylene chloride was removed under reduced pressure and the residue was dissolved in 10 ml of ethyl acetate. Ether was added and the crystals which appeared were filtered off. 4195 mg of 2,2,2-trichloroethyl ester of 7- [DN-tert-butoxycarbonyl ^ -G-mesylaminophenyDglycinamido] -? - methylO-cephem ^ -carboxylic acid, mp 204-205 ° C. (decomposition) were obtained.

R) To a suspension of 26.8 g of the hydrochloride of 2.2,2-Trichlorätήyl-7-arnino-3-methyl-3-cephem-4-carboxylate in 500 ml of dry methylene chloride were gradually a solution of 7 g of triethylamine in dry Methylene chloride (25 ml) and then a solution of 2.14 g of 2,6-lutidine in 25 ml of methylene chloride Ice cooling added. In addition, 26.0 g of N-tert-butoxycarbonyl-2- (3-mesylaminophenyl) -D-glycine and then 15 g of dicyclohexylcarbodiimide was gradually added, and the mixture was allowed to stand under ice cooling for 1.5 hours touched. After removing an insoluble product

ίο the filtrate was filtered four times with ice-cold 5% hydrochloric acid (100 ml), once with water, three times with 10% aqueous sodium carbide solution and washed once with an aqueous saturated sodium chloride solution and then over magnesium sulfate dried. The solution was treated with activated charcoal and the solvent was reduced under reduced pressure Pressure removed. The residue was dissolved in 100 ml of ethyl acetate and overnight at room temperature ditched. The crystals which appeared were filtered off, whereby 31.3 g of 2,2,2-trichloroethyl ester of 7- [DN-tert-butoxycarbonyl-2- (3-mesylaminophenyl) -glycinamido] -3-methyl-3-cephem-4- carboxylic acid were obtained in the form of colorless plates. 189 to 191 ° C (decomposition).

Preparation of the 7- [D-N-tert-butoxycarbonyl-2-

(3-mesylaminophenyl) glycine amido] -

3-methy! -3-cephem -4 -carboxylic acid:

C) The 2,2,2-trichloroethyl-7- [D-N-tert-butoxycarbonyl-2- (3-mesylaminophenyli-g] ycinami- do] -3-methyl-3-cephem-4-carboxylate (3985 mg) was in 17 ml of dimethylformamide dissolved. 5.0 ml of acetic acid and 3985 mg of zinc powder were added to the solution Ice cooling was added with stirring, and the mixture was stirred at the same temperature for 2 hours.

After an insoluble product was filtered off, the filtrate was washed with 3 ml of dimethylformamide. The washing liquid and the previously obtained filtrate were combined with each other and while cooling with ice placed in 100 ml of 5% hydrochloric acid. 50 ml of water was added and the resulting The mixture was extracted three times with ethyl acetate (50 ml). The extract was washed with water and back-extracted three times with a 5% aqueous solution (50 ml) of sodium bicarbonate, and the aqueous Layer was acidified with hydrochloric acid. The aqueous solution was back-extracted again with ethyl acetate, and the extract was washed with water and dried. The solvent was reduced under The pressure was removed and the residue was dissolved in 10 ml of ethyl acetate. The solution was at room temperature allowed to stand for an hour and then ether was added to the solution. There were crystals of 7- [D-N-tert-butoxycarbonyl ^ -O-mesylaminopheyD-glycinamido] -3-methyl-3-cephem-4-carboxylic acid (2687 mg), mp 187-189 ° C (decomposition).

D) The 2,2,2-trithloroethyl-7- [D-tert-butoxycarbonyl ^ -O-mesylaminopheiiyD-glycinamido] -3-methyl-3-cephem-4-carboxylate obtained under B) (12.01 g) was dissolved in 40 ml of dimethylformamide. 15 ml of glacial acetic acid and 12 g of zinc powder were gradually added to the solution while cooling with ice was added, and the mixture was stirred at the same temperature for one hour. after the When the reaction was over, an insoluble product was filtered off and washed with ethyl acetate. The filtrate and

^sr> the washing liquid wedges were einge.uossen under ice-cooling in 3 ^q nige hydrochloric acid (300 ml). The mixture was extracted three times with ethyl acetate (150 ml). The ethyl acetate extract was washed with water

see and then three times with a 5% aqueous Back extracted sodium bicarbonate solution (150 ml). The aqueous solution was washed with ethyl acetate and Adjusted to pH 2 with 1096 hydrochloric acid. The obtained product was used three times extracted with 150 ml of ethyl acetate. The extract was washed with water and dried over magnesium sulfate, and the solvent was removed under reduced pressure. The crystals appearing were with Ethyl acetate and washed with ether. 8.38 g of 7- [D-N-tert-butoxycarbonyl-2- (3-mesylaminophenyl) -glycineamido] -3-methyl-3-cephem-4 -carboxylic acid, m.p. 188 to 189 ° C (decomposition) obtained.

Example 2

IR.

ι (cm- ¹ ): 3330, 3290, 3240, 1769, 1720, 1690, 1668, 1524, 1308, 1220, 1146,912,890,772

NMR.

ODMSOd ₆

, (ppm): 1.40 (9H, s), 2.00 (3H, s) 2.99 (3H, s), 3.37 (2H, broad s), 4.96 (IH, d, J = 4.4 Hz, 5.30 (1H, broad d, J = 8Hz), 5.63 (IH, d, d, J = 4Hz, 7Hz), 6.90 ~ 7.50 (4H, m)

Preparation of 7- [D-2-i 3-MesylaminophenyD-glycinamido] -3-methyl-3-cephem-4-carboxylic acid:

E) 8.28 g of the 7- [D-N-tert-butoxycarbonyl-2- (3-mesylamino) -glycineamido] o-methyl-3-cephem-4-carboxylic acid obtained above were added to 140 ml of formic acid while cooling with ice, and then the Mixture stirred at room temperature for 1.5 hours. After removing the formic acid at 35 ° C under reduced The residue was dissolved in 30 ml of 5% hydrochloric acid under pressure. The solution was with Washed 20 ml of Ethyhicetat, treated with activated charcoal and then adjusted to pH 3 with a 10% aqueous solution of sodium hydroxide. The occurring crystals were filtered, washed with water and dried, whereby 6.18 g of 7- [D-2- (3-mesylaminophenyl) glycine amidol ^ - 'nethyl-S-cepheirM-carboxylic acid, M.p. 199 to 199.5 ° C (decomposition).

[ct] £ = + 131 ° (O.k. HCl, c = 1)

UV.

λ pH 6.4 phosphate buffer

max. 263. ιτιμ, Ε = ■ 172
λ pH 6.4 phosphate piiffer

inf228 πιμ. Ε 299

NMR. 2.08 (3H, s), 3. 19 (3H, s). 60 IR. (cm- ¹ ): <5d ₂ o - Dei (ppm): 3.::i. , 3.44 VNujol (2H, ABq, J = 18 Hz), 5.04 (IH, d, J = = 5Hz), NMR. (ppm): 537 (IH, 3), OCDCl ₃ 5.67 (IH, d, J = = 5Hz), 7.4 - - 7.67 (4H , m)

IR.

(cm- ¹ ): 3610, 3510, 3330, 1750, 1700, 1600, 1526, 1380, 1366, 1328.

A) Preparation of the starting compound N-tert-butoxycarbonyl-2- (3-ethanesulfonamidophenyI) -D-glycine

3.99 g of N-tert-butoxycarbonyl-2- (3-aminophenyl) -D-glycine and 6.12 g of N, N-bis (trimethylsilyl) acetamine were added to 40 ml of methylene chloride was added, and the resulting mixture was allowed to stand at room temperature for 2 hours touched. To the mixture obtained were under

ίο Ice cooling 2.4 g pyrldine and 3.84 g ethanesulfonyl chloride added dropwise. Stirring was continued for 2 hours at 0 to 5 ° C and then for 1 hour at room temperature continued. The reaction mixture was washed twice with 20 ml of 2% hydrochloric acid, twice with 20 ml

is water and washed once with a saturated aqueous sodium chloride solution in the order given. The methylene chloride layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether, and 4.4 g of N-tert-butoxycarbonyl-2- (3-ethanesulfonamidophenyl) -D-
glycine in the form of a powder: IR (film ν cm " ¹ : 3230, 1720, 1680; NMR (CDCl3,) δ ppm: 1.18 (3H, t, J = 7.5 Hz), 1.36 (9H , s), 3.05 (2H, q, J = 7.5 Hz), 3.16 (1H, broad, s), 7.23 (4H, s), 7.71 (IH, broad, s), 8.59 (IH, broad s).

B) A solution of 1.32 g of ethyl chloroformate in 20 ml of dry methylene chloride was cooled to -10 ° C. A solution of 4.4 g of N-tert-butoxycarbonyl-2- (3-ethanesulfonamidophenyl) -D-gylcine was added dropwise to this solution over a period of 10 minutes and 1.22 g of triethylamine in 20 ml of methylene chloride and 2 drops of N, N-dimethylbenzylamine was added, and then the mixture was stirred at room temperature for one hour.

^J5 other hand, 3.82 g of 2,2,2-trichloroethyl 7-amino-3-methyl-3-cephem-4-carboxylic acid, 0.9 g of tri-ethylamine and 0.12 g of N, O-bis (trimethylsilyl ) acetamide dissolved in 40 ml of absolute methylene chloride. The solution was added dropwise over 10 minutes to the mixture prepared above at a temperature of -15 ° C. The resulting solution was stirred at the same temperature for 2 hours and then washed twice with 2% hydrochloric acid, an aqueous solution of sodium bicarbonate and an aqueous saturated solution of sodium chloride and dried over magnesium sulfate. After removing the solvent from the solution under reduced pressure, the residue was pulverized with a small amount of ethanol, whereby 4.2 g of the 2,2,2-trichloroethyl ester of 7- [DN-tert-butoxycarbonyl-2- (3- äihansuifonamiuophcny!) - giyciriarn! uOj-3-methyl-3-ccphem-4-carboxylic acid were obtained in the form of colorless crystals. 117 ° C.

3400, 3230, 1762, 1735, 1690

1.28 (3H, t, J = 7Hz), 1.38
(9H, s),

2.16 (3H, s), 2.75 ~ 3.50
(4H, m),

4.82, 4.95 (2H, ABq, J = 12Hz),

4.95 (IH, d, J = 5Hz), 5.24
(IH, d, J = 6Hz), 5.81 (IH, d, d,
J = 5Hz, J = 8Hz), 7.25 (4H, s).

The 2,2,2-trichloroethyl-7- [D-N-tert-butoxycarbonyl-amino ^ -O-ethanesulfonamidophenyD-glycinamidolO-methyl-S-cephem ^ -carboxylate obtained above (4.2 g) was dissolved in a mixture of 15 ml of absolute dimethylformamide and 45 ml of acetic acid. 3.6 g zinc powder were added to the solution under ice-cooling, and the mixture was stirred for two hours. After this the zinc powder was filtered off, the filtrate was dissolved into a mixture of 40 ml of 2% hydrochloric acid and 40 ml of ethyl acetate were poured, and the ethyl acetate layer was separated. The aqueous layer was extracted with 20 ml of ethyl acetate. The ethyl acetate layer and the extract were combined with each other, with 20 ml of 2% hydrochloric acid and 20 ml of an aqueous saturated solution of sodium chloride in succession washed and dried over magnesium sulfate. The solvent was reduced from the solution The pressure was removed and the residue was washed with diisopropyl ether, 3.2 g of 7- [D-N-tert-butoxycarbonyl-2- (3-ethanesulfonamidophenyl) -glycine-amidol-S-methylO-cephem ^ -carboxylic acid in the form of an oily product.

IR.

NMR.

<5cd ₃ od (ppm):

3300, 1765, 1700

1.22 (3H, t, J = 7.5Hz), 2.09 (3H, s), 2.75 ~ 3.75 (4H, m), 4.96 (IH, d, J = 4.5Hz), 5.26 (IH, s), 5.67 (IH, d, J = 4.5Hz), 7.25 (4H, s).

A solution of 3.1 g of the 7- [D-N-tert-butoxycarbonyl-2- (3-ethanesulfonamidophenyl) - obtained above glycinamidol-S-methyl ^ -cephem ^ -carboxylic acid in 15 ml Formic acid was stirred at room temperature for 2 hours. The formic acid was at room temperature removed from solution under reduced pressure. The residue was pulverized with ether and filtered. That resulting powder was added to 20 ml of a 10% aqueous solution of acetonitrile for one hour Stirred under ice-cooling, and then the appearing crystals were filtered off. 1.7 g of 7- [D-2- (3-ethanesulfonamidophenyD-glycineamidol-S-methylO-cephem-4-carboxylic acid obtained in the form of white crystals. Mp 179 to 182 ° C (decomposition).

IR. 1770, 1695, 1600 , t, J = 7.5Hz) vnujoi (cm- '): s), 2.75 ~ 3.67 NMR. (ppm): 1.29 C3H .96 (IH, d i, J = 1.90 (3H, .25 (lH, s), 5.59 (4H, m), 4 = 4.5Hz), 7.34 4.5Hz), 5 (IH, d, J (4H, s)

Example 3

(1) To a solution of 8.0 g of N-tert-butoxycarbonyl-2- (3-amino-4-hydroxyphenyl) -D-glycine in 150 ml of methylene chloride were 11.5 g of bis (trimethylsilyl) acetamide was added and the resulting solution was stirred at room temperature for 30 minutes. After cooling down with ice, 4.5 g of pyridine was added, and then 6.5 g of methanesulfonyl chloride was added to the obtained one Mixture added dropwise. Stirring was continued for 30 minutes with ice-cooling and then for 2 hours at Room temperature continued. The reaction mixture was concentrated under reduced pressure. The residue was mixed with ethyl acetate and water, made acidic with phosphoric acid and the ethyl acetate layer was separated from the water layer. The ethyl acetate layer was washed with an aqueous sodium hydrogen carbonate solution back extracted and the water layer was separated, acidified with phosphoric acid and

back-extracted again with ethyl acetate. The ethyl acetate extract was washed with water, dried and treated with activated charcoal. The resulting solution was then concentrated to give 6.0 g of N-tert-butoxycarbonyl-2- (3-mesylamino-4-hydroxyphenyl) -D-glycine;

IR (chloroform) ν cm- ': 1730 (shoulder), 1715; NMR (D ₂ O-NaHCO ₃ ) δ ppm: 1.4 (9H, s), 3.05 (3H, s), 4.83 (1H, s), 6.87 (1H, d, J = 8Hz ).

(2) 2.0 g of dicyclohexylcarbodiimide were cooled with ice and with stirring to a solution of 5.2 g of N-tert-butoxycarbonyl ^ -O-mesylamino ^ -hydroxyphe-
nyl) -D-glycine, 5.52 g of 2,2,2-trichloroethyl-7-amino-3-methyl ^ -cephem ^ -carboxylate hydrochloride and 1.74 g of 2,6-lutidin in 180 ml of absolute methylene chloride . The resulting mixture was stirred for one hour at the same temperature and additionally stirred for three hours at room temperature. An insoluble product was filtered off, and the filtrate was condensed under reduced pressure. Ethyl acetate was added to the residue, after which the pH of the solution was adjusted

adjusted to about 2 with phosphoric acid. The ethyl acetate layer was separated, washed with water and dried over magnesium sulfate. After the ethyl acetate had been removed from the solution under reduced pressure, the residue was pulverized with isopropyl ether, 6.75 g of 2,2,2-trichloroethyl ester of 7- [N-tert-butoxycarbonyl-2- (3-mesylamino-4- hydroxyphenyI) -D-
glycinamidol-S-methyl ^ -cephem - ^ - carboxylic acid. The product was recrystallized from ethyl acetate, whereby the purified substance, F. was obtained from 185 to 188.5 ⁰ C (decomposition).

IR.

NMR.

1766

(ppm): 1.40 (9H, s), 2.16 (3H, s), 3.01
(3H, s), 3.34, 3.59 (2H, AB-q,
J = 18Hz), 4.87,5.07 (2H, AB-q,
J = 12.5Hz), 5.07 (IH, d, J =
4.5Hz), 5.35 (IH, d, J = 8Hz),
5.80 (IH, d, d, J = 4.5 Hz, 8Hz),
6.3-6.5 (IH, m), 6.90 (IH, d,
J = 8Hz), 7.20 (IH, d, d,
J = 2Hz, 8Hz), 7.52 (IH, d, J =
2Hz), 8.0-8.3 (2H, m)

(3) 3.5 ml of acetic acid and 2.6 g of zinc powder were cooled with ice to form a solution of 3.0 g of 2,2,2-trichloroethyl ^ -tN-tert.-butoxycarbonyW-G-mesylamino ^ - hydroxyphenyl) -D-gly cinamido] -3-methyl -3-cephem -4-carboxylate in 9 ml of dimethylformamide. That The mixture was stirred at the same temperature for 40 minutes. After the end of the reaction, the zinc powder became filtered off and washed with a small amount of dimethylforamide, and the filtrate and the washing liquids were combined with each other. Ethyl acetate and dilute phosphorus were added to the mixture.

acid was added and the ethyl acetate layer was separated. The extract was washed with water and back-extracted with an aqueous solution of sodium bicarbonate. The aqueous solution was treated with hydrochloric acid acidified and then extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was washed with ether, whereby 1.58 g of 7- [N-tert-butoxycarbonyl-2- (3-mesylamino-4-hydroxyphenyl) -D-glycolnamldo] -3-methyl-3-cephem-4-car - acid was obtained in the form of a powdery product.

IR.

ν Nujoi (cm- '): 1765

NMR.

<5 D ₂ O ₊ NaHCo ₃ (ppm): 1.40 (9H, s), 1.90 (3H, s),

3.05 (3H, s), 3.00, 3.39 (2H, AB-q, J = 18Hz), 4.90 (lH, d, J = 4.5Hz), 5.08 (IH, s),
5.52 (IH, d, J = 4.5Hz), 6.8-7.4 (3H, m)

(4) A solution of 1.45 g of 7- [N-tert-butoxycarbonyl-2- (3-mesylamino-4-hydroxyphenyl) -D-glycinamido] -3-
methyl-3-cephem-4-carboxylic acid in 6 ml of formic acid was stirred for 1.5 hours at 4O ⁰ C. After the completion of the reaction, formic acid was removed under reduced pressure, and then 30 ml of acetonitrile and 0.5 ml of water were added to the residue with stirring, and the mixture was stirred for 30 minutes. The powder obtained was filtered off and washed with acetonitrile and with ether, 1.13 g of 7- [2- (3-mesylamino-4-hydroxyphenyl) -D-glycinamido / -3-methyl-3-cephem-4-carboxylic acid, M.p. 186 to 192 ° C (decomposition).

IR.

(cm- ¹ ): 1760

NMR.

<5 d ₂ c + dci (ppm):

2.12 (3H, s), 3.20 (3H, s),

3.25, 3.50 (2H, AB-q,

J = 18Hz), 5.09 (IH, d, J

= 4.5Hz),

5.33 (IH, s), 5.66 (IH, d,

J = 4.5Hz), 7.15 (IH, d,

J = 8Hz), 7.40 (IH, d, d, J =

2Hz, 8Hz),

7.53 (IH, d, J = 2Hz).

Example 4

(1) To a solution of 7.0 g of N-tert-butoxycarbonyi-2- (3-aminophenyl) -D-glycine and 2.92 g of triethylamine in 100 ml of methylene chloride, which had cooled to 5 ° C, a solution of 3.0 g of methyl isocyanate in 25 ml of methylene chloride was added dropwise within 5 minutes, and the resulting mixture was stirred at room temperature for 5 hours. After removing the solvent by distillation the residue was dissolved in ethyl acetate and with a 2M citric acid solution washed. The organic solvent layer was washed with water and with an aqueous sodium hydrogen carbonate solution extracted. The water layer

was separated off, washed with ether and adjusted to pH 6 with 10% sulfuric acid. The resulting solution was adjusted to pH 3 to 4 with citric acid, salted out and extracted with ether. The ether extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give N-tert-butoxycarbonyl ^ - [3- (3-methylureido) phenyl] -D-glycine (5.7 g) in the form a foamy material; NMR (DMSO-d ₆ ) 3 ppm:

1.37 (9H, s), 2.54 (3H, d, J = 4.5 Hz), 4.97 (1H, d, J = 8 Hz), 5.96 (1H, d, J = 4.5 Hz), 6.7 to 7.6 (6H, m), 8.47 (1HsS) ^ a] ₀ = 111 ° (9996 ethanol).

(2) To a suspension of 3.61 g of the hydrochloride of 2,2,2-trichloroethy-7-amino-3-methyl-3-cephern-4-carboxylate 0.95 g of triethylamine were added in a portion at 5 ° C. in 50 ml of methylene chloride. To the The mixture gradually became 3.37 g of N-tert-butoxycarbonyl-2- [3- (3-methylureido) phenyl] -D-glycine and 2.88 g of RN'-Dlcyclohexylcarbodiimld added, and the obtained mixture was stirred for one hour at room temperature. An insoluble product was filtered off, and the filtrate was concentrated under reduced pressure. Thereafter, ethyl acetate was added to the residue admitted. The resulting solution was washed three times with 5% hydrochloric acid, with water, with a aqueous solution of sodium bicarbonate (three times), with water and with an aqueous solution of sodium chloride washed (three times), dried and then concentrated. The concentrate was left in a cold environment, and the obtained crystals were filtered off. 3.96 g of 2,2,2-trichloroethyl ester 7- [N-tert-butoxycarbonyl ^ -Ö-dnethylureidoiphenyO-D-glycinamidolO-methylO-cephem ^ -carboxylic acid, M.p. 152 to 160 ° C (decomposition).

IR.

ν Ni «oi (cm- '): 3320, 1782, 1731

NMR.
δ DMS0-d ₆

1.42 (9H, s), 2.08 (3H, s),
2.63 (3H, d, J = 5Hz), 3.47
(2H, t, J = 20Hz)., 4.8-5.4
(4H, m), 5.95 (IH, d,
J = 5Hz), 6.7-7.6 (4H, m),
8.37 (IH, s), 9.05 (IH, d,
J = 7Hz)

(3) 5.7 g of zinc powder and 5.7 ml of glacial acetic acid were made into a solution of 5.7 g at a temperature of 5 ° C 2,2,2-Trichloroethyl-7- [N-tert-butoxycarbonyl-2- {3- (3-methylureldoi-phenyl-D-glycinamldolO-methyl-S-cephem-4-carboxylate given in 57 ml of dimethylformamide. The mixture was stirred at room temperature for one hour and filtered. Some ice, 5% hydrochloric acid and ethyl acetate were added to the filtrate. the organic layer was separated, washed twice with water and with an aqueous solution of sodium bicarbonate back extracted. The aqueous layer was separated, extracted with ethyl acetate, with 5% Acidified hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then the solvent was removed from the extract.

In this 3.29 g of 7- [N-tert-butoxycarbonyl-2- {3- (3-methylureidoiphenylj-D-glycinamidol-S-methyU-cephem-4-carboxylic acid, mp 143-150 ⁰ C (decomposition) obtain.

IR.

(cm- ¹ ): 3370, 1780

NMR.

ÖDMSO-d,

(ppm): 1.38 (9H, s), 1.99 (3H, s),

2.63 (3H, d, J = 5Hz), 3.28, 3.45 (2H, AB-q, J = 18Hz),

4.96 (IH, d, J = 5Hz), 5.28 (IH, wide d, J = 8Hz), 5.62 (IH, d, d, J = 5Hz, 8Hz),

5.97 (IH, broad d, J = 5 Hz), 6.8-7.6 (4H, m), 8.44 (IH, s), 9.02 (IH, wide d, J = 8Hz)

(4) 3.18 g of 7- [N-tert-butoxycarbonyl-2- {3- (3-methylureidophenyl} -D-glycinamldo] -3-methyl-3-cephem-4-carboxylic acid were added to 60 ml of formic acid from 10 ° C, and the mixture was stirred at room temperature for two hours and then concentrated under reduced pressure. The residue was pulverized with 70 ml of ether, and the filtered powder was added to 10 ml of 596 ml of aqueous acetonitrile, stirred for 30 minutes and then filtered 2.2 g of 7- [2- {3- (3-methylureido) phenyl} -D-glyclnamidolO-methyl o-cephem ^ -carboxylic acid in the form of crystals. F. 215 to 218 ⁰ C (decomposition).

IR.

VNujoi (cm- '): 3350, 1760

NMR.

Od ₂ O + Da (ppm): 2.2 (3H, s), 2.85 (3H, s), 3.23, 3.51 <2H, AB-q, J = 19Hz), 4.95 (IH, d, J = 5Hz), 5.33 (IH, s), 5 7 (IH, d, J = 5Hz), 7.2-7.7 (4H, m)

Example 5

a) The sodium salt (4.76 g) of N- (1-ethoxycarbonyl-1-propen-2-yl) -2- (3-mesylaminophenyl) -D-glycine was suspended in methylene chloride (35 ml). N, N-dimethylbenzylamine was added dropwise to this suspension (2 drops) and the methylene chloride solution (6 ml) containing ethyl chlorofo-mat (2.75 g) at -14 to -16 ° C and the mixture was stirred at the same temperature for 10 minutes and then cooled to -50 ° C. On the other hand, 7-amino-S-methyl ^ -cephem ^ -carboxylic acid became the suspension (2.25 g) in methanol (45 ml) triethylamine (4.3 ml) was added and the mixture was allowed to stand at room temperature for 30 minutes touched. Methanol (13.5 ml) containing hydrochloric acid (C. 795 mmol / ml) was added to the solution. These Solution was added dropwise to the solution obtained as described above over 10 minutes at -50 ± 5 ° C, and the mixture was 1 hour at the same temperature, 2 hours at -30 ° C and then Stirred at -15 ° C for 30 minutes. The solvent was removed from the resulting solution under reduced pressure removed. The residue was dissolved in ethyl acetate and aqueous sodium bicarbonate, and the aqueous layer was separated. The organic layer was extracted with aqueous sodium bicarbonate and the aqueous Layers were combined and then adjusted to pH 3.5 with 10% hydrochloric acid. The solution was made twice washed with ethyl acetate and column chromatography using a nonionic adsorption resin (150 ml). The column

15 was washed with water and eluted with 10% aqueous isopropyl alcohol. The eluate was concentrated to a volume of 200 ml under reduced pressure and freeze-dried to give a powder (2.96 g) of 7- [2- (3-mesylaminophenyl) -D-glyclnamido] -3-methyl-3-cephem- 4-carboxylic acid was obtained.

The product was dissolved in 1N hydrochloric acid, and the The solution was adjusted to pH 4 to 4.5 with sodium hydroxide solution. After the solution was left to stand in the cold, crystals precipitated became collected by filtration and dried to give colorless needles of the desired pure compound became. 198 to 200 ° C (decomposition).

I.R.

Nujoi (cm- '): 3310, 1747, 1695, 1600, 1140 N.M.R.

DCl + D ₂ O (ppm)

20th

2.06 (3H, s), 3.17 (3H, s), 3.13, 3.50 (2H, AB-q, J = 18Hz), 5.0 (lH, d, J = 4.5Hz), 5.41 (IH, s), 5.65 (IH, d, J = 4.5Hz), 7.46 (4H, m)

U.V.

pH 6.4 phosphate buffer

max 263 m, E = 170.5

b) To a solution of the sodium salt (955.7 mg) of N-d-methoxycarbonyl-1-propene ^ -yD ^ -O-mesylaminophenyl) -D-glycine in ethyl acetate (10 ml) were bis- (TrimethylsilyD-acetamld (2 drops) and isobutyl chloroformate (393.3 mg) and the mixture was added Stirred for 1 hour. A suspension of 2,2,2-trichloroethyl ^ -amino-S-methylO-cephem ^ -carboxylate-hydro- chloride (764 mg), triethylamine (212 mg) and ethyl acetate (15 ml) were added, and the mixture was at the same Stirred temperature for 2 hours. After in-hydrochloric acid (4 ml) was added, the organic Removed solvent under reduced pressure. Methylene chloride (5 ml) was added to the residue, and the solution was stirred at room temperature for 1 hour. The crystal precipitated was collected by filtration collected and dried over phosphorus pentoxide, 2,2,2-trichloroethyl-7- [2- (3-mesylaminophenyl) -D-glycine amidol-S-methyl-S-cephem ^ -carboxylate hydrochloride (1.0525 g), mp 150-155 ° C (decomposition).

LR. (cm- '): 3300,3200,1777, 1730, 1698, Nujol 1680, 1150, .R. N.M. ^D (npm): 2.15 (3H, s), 3.02 (3H, s), CD ₁ O

3.18, 3.56 (2H, AB-q, J = 18Hz), 4.59, 5.08 (2H. AB-q, J = 12Hz), 5.03 (IH, d, J = 4.5Hz), 5.10 (IH, s), 5.73 (IH. D. J = 4.5Hz). 7.25 - 7.50 (4H, m)

U.V.

CH3OH

max 270 m, E = 96.5

To a solution of 2,2,2-trichloroethyl-7- (2- (3-mesylaminophenyl) -D-glyclnamido] -3-methyl-3-cephem-4-car- Boxylate hydrochloride (517.8 mg) in 90% acetic acid (5 ml) was added zinc powder (1 g) and the mixture was stirred for 3 hours while cooling with ice.

tion mixture was filtered and twice with 90% Acetic acid (5 ml) washed. The filtrate and wash liquors were combined and under reduced pressure concentrated. Toluene was added to the residue and then the toluene was removed under reduced pressure removed. The residue was dissolved in water (3 ml) and ethyl acetate (6 ml) and the solution was washed with 2C% sodium hydroxide solution adjusted to pH 4. After the solution was shaken, the aqueous became Layer separated, washed with ethyl acetate and treated with activated charcoal. The solution was made up to volume of 2 ml and allowed to crystallize with ice-cooling. The precipitated crystals were collected by filtration and washed successively with water, acetone and finally ether, wherein 7- [2- (3-mesylaminophenyl) -D-glycinamido] -3-methyl-3-cephem-4-carboxylic acid (212.4 mg), mp 194.5-195.5 ° C (decomposition).

Comparative experiments

To demonstrate the therapeutic superiority of the 7- (substituted phenylglycinamldo) -3-methyl-3-cephem-4-carboxylic acid derivatives according to the invention the following comparative experiments A and B were carried out in which the compounds according to the invention according to Examples 1, 3 and 5, namely:

Example 1:

7- [D- (3-mesylaminophenyl) glycine amido] -3-

methyl-3-cephem-4-carboxylic acid

Example 3:

7- [2- (3-mesylamino-4-hydroxyphenyl) -D-glycine-

amido] -3-methyl-3-cephem-4-carboxylic acid

Example 4:

7- [2- {3- (3-methylureido) phenyl) -D-glycine-

amido] -3-methyl-3-cephem-4-carboxylic acid

with known comparison products of the same direction of action, namely

Cefadroxil (according to claim 12 of GB-PS 12 40 687),

Cefalotin

Cefazolin

Cefamandol

with regard to their effectiveness against pathogenic microorganisms and with regard to their absorption rates when administered orally were compared.

(A) Comparison of the effectiveness against pathogenic microorganisms based on the minimum inhibitory concentrations (MIC) of the compared cephalosporal innervates.

Test procedure

The antibacterial invltro-Aktlvitäi was under Use the two-fold agar plate dilution procedure described below certainly:

a loop filling of an overnight culture of each test strain in a tryptlcase soy broth (18 ^g viable cells per ml) was streaked onto a heart infuslons agar (HI agar) containing graduated concentrations of the respective test compound, and the minimum inhibitory concentration was applied (MIC), expressed in Ug / ml, determined after incubation for 20 hours at 37 ° C.

From the results below it can be seen that the compounds of the invention with respect to Their antibacterial activity was clearly superior to the comparative product Cefadroxil.

Test results (MIC. Μ% / τη \)

Test connection

Tests
Klebsieila pneumoniae
417

example 1 Example 3

Example 4
Cefadroxil

3.13
12.5
12.5
25th

(B) Determination of the absorption rates of each other compared cefalosporin derivatives when administered orally based on urine and biliary excretion in rats

Test procedure
(a) Urine excretion

The urine of rats to which 100 mg of the test compound per kg of body weight was orally administered were in a urine collector, 0 to 6 and 6 to 24 hours after the oral. Administration collected. the Concentration of the solid compound in the urine samples was determined in a bioassay with a standard buffer PH 7.0 was determined, and from this the urine excretion within 24 hours was calculated.

(b) biliary excision

Rats anesthetized with phentobarbital were used in the The patient was fixed in the supine position and a polyethylene cannula was inserted into the biliary canal. The bile samples were 0 to 3, 3 to 6 and 6 to 24 hours after the oral administration of 100 mg of the test compound per kg of body weight collected.

The levels of the test compounds in the bile samples were prepared using standard solutions containing an M / 15 phosphate buffer (pH 7.0) were determined, and then the bile excretion within 24 hours was calculated.

Test results

Test connection R ¹

R ² M * A * B

example 1
Example 3
Example 4
so cefalotin
Cefazolin
Cefamandol
Cefadroxil

CH ₃ SO ₂ NH
CH ₃ SO ₂ NH

H H 62.1 67.5

OH H 85.8 no values

CH ₃ NHCONH HH

77.9 5.9

0.3 no values 10.5 1.8

6.1 26.8
79.0 1.74

* A: urine excretion within 24 hours (%)
* B: biliary excretion within 24 hours (%)

From the above results it can be seen that the compounds according to the invention are valuable and are effective cephalosporins that can be administered orally. They are given orally Absorbs significantly better than the comparison products Cefalotin, Cefazolin and Cefamandol, with the absorption rates of the compounds according to the invention are comparable with those of the comparative product Cefadroxil, which they far surpass in terms of antibacterial effectiveness (see experiment A above).

308117/83

Claims (1)

Patent claims: 1. 7- (Substituted phenylglycine amido) -3-methyl-3-cephem-4-carboxylic acid deri vate, characterized by the general formula CH-CONH NH ₂ 10